Angiogenesis, the formation of new blood vessels from pre-existing vasculature, plays a role in the pathogenesis of many diseases, including ocular diseases such as age-related macular degeneration (AMD) or diabetic macular edema (DME). Vascular endothelial growth factor (VEGF) plays a role in the regulation of normal and abnormal angiogenesis (Ferrara et al, (1997) Endoer. Rev. 18:4-25). Several anti-VEGF agents are provided in the art, e.g., in U.S. Pat. No. 7,169,901, which discloses VEGF antibodies for inhibiting VEGF-induced cell proliferation, and U.S. Pat. No. 7,070,959, which discloses isolated nucleic acid molecules encoding fusion proteins capable of binding VEGF.
Targeting VEGF with currently available therapeutics is not effective in all patients or for all diseases associated with inflammation and/or angiogenesis. A significant population of non-responders present following anti-VEGF monotherapy, and the disease prevalence will only increase as the aging population increases globally.
A currently preferred treatment for wet AMD consists of intravitreal injections of an anti-VEGF agent. However, although anti-VEGF therapy reduces choroidal neovascularization, it does not have an effect on regression of the mature vasculature. Also, current agents do not provide an anti-fibrotic effect, so that once scarring of the retina occurs; visual acuity cannot be recovered. Other limitations of the existing treatments regimens include patient discomfort, the need for repeat injections with inherent complications including endophthalmitis, retinal tear and detachment, intraocular hemorrhage, and cataract formation. There is a substantial time burden on ophthalmologists to provide monthly intravitreal treatment and optical coherence tomography (OCT) measurements on a large volume patients. As a result, there is a significant medical and economic need for an AMD therapeutic with greater efficacy, or that can be delivered less frequently and still achieve optimal efficacy.
Platelet-derived growth factor (PDGF) is a growth factor involved in the regulation of blood vessels from pre-existing vessel tissue. PDGF binds to receptors on pericytes in newly-forming abnormal blood vessels. This may contribute to neovascularization of abnormal blood vessels by providing a protective perictye coating, for example, during ocular disorders such as wet AMD.
Engineered proteins, such as antibodies, fragments, and multispecific binding proteins capable of binding two or more antigens, are known in the art. Such multispecific binding proteins can be generated using cell fusion, chemical conjugation, or recombinant DNA techniques. There are a variety of multispecific binding protein structures known in the art and many structures and methods have distinct disadvantages.
Bispecific antibodies have been produced using quadroma technology. Bispecific antibodies can also be produced by chemical conjugation of two different mAbs. Other approaches include coupling of two parental antibodies with a hetero-bifunctional crosslinker, production of tandem single-chain Fv molecules, diabodies, bispecific diabodies, single-chain diabodies, and di-diabodies. In addition, a multivalent antibody construct comprising two Fab repeats in the heavy chain of an IgG and capable of binding four antigen molecules has been described (see PCT Publication No. WO 01/77342 and Miller et al. (2003) J. Immunol. 170(9):4854-61).
U.S. Pat. No. 7,612,181 (incorporated herein by reference in its entirety) provides a novel family of binding proteins capable of binding two or more antigens with high affinity, which are called dual variable domain binding proteins (DVD-Ig binding protein) or dual variable domain immunoglobulins (DVD-Ig). DVD-Ig molecules are binding proteins that may be used to bind two distinct epitopes on the same molecule or two different molecules simultaneously. DVD-Ig molecules are unique binding proteins comprised of two variable domains fused to N-terminal constant regions. The variable domains may be directly fused to one another or connected via synthetic peptide linkers of assorted length and amino acid composition. DVD-Ig binding proteins may be engineered with intact and functional Fc domains, or otherwise modified constant domains, allowing them to mediate appropriate effector functions and exhibit other desired properties. The DVD-Ig format, due to its flexibility of choice of variable domain pair, orientation of two antigen-binding domains, and the length of the linker that joins them, may provide novel therapeutic modalities.
Accordingly, while VEGF monotherapy has had some success in the art, there remains a need for constructs exhibiting better targeting, efficiency, and/or efficacy in binding to VEGF, as well as improved targeting of other pathways involved in inflammation (such as ocular inflammation), e.g., the PDGF pathway. Improved targeting of either of these molecules, alone or in combination, may lead to improvements in, e.g., preventing, diagnosing, and/or treating disorders such as angiogenic, inflammatory, and/or ocular disorders. Also, while a variety of structures have been provided in the art, with various advantages and disadvantages, new variable domain sequences can further improve the properties of binding proteins targeting VEGF and/or PDGF, or their cognate receptors.